Biological warfare pathogens (BWP) will potentially have severe toxicity and broad antigenic variation from deliberate manipulations and may be transmissible by numerous routes of entry, thus requiring successful vaccines to induce a much higher degree of immune protection than is needed for most ordinary pathogens. Pulmonary, gastrointestinal, and cutaneous surfaces have the highest risk of exposure. Since systemic immunity often develop responses independently of the common mucosal immune system, vaccines must be designed to elicit the mucosal effector cells that can disseminate after sensitization in one compartment to other surface tissues, enabling vaccination at an accessible site to induce immunologic resistance at other sites as well. Unlike other vaccine targets, for which substantial local pathogen replication may be tolerable before the systemic immune response controls and eradicates the infection, the immune response induced by a BWP vaccine should ideally prevent toxicity or infection entirely, or rapidly kill any pathogens or infected cells in the mucosa before extensive replication occurs. The skin, lung, and gut contain the largest surface areas of potential exposure, and are thus the natural targets that must be protected with vigorous immune responses to microbial pathogens or pathogenic products. To achieve this goal, vaccine strategies must be devised that are highly flexible antigenically and can be delivered in such a way that the mucosal immune system is strongly stimulated. Unfortunately, traditional vaccine methods using purified peptides, protein subunits, and/or attenuated or inactivated pathogens do not have all these immunological features. Furthermore, since the nature of BWP will not be precisely predictable, a general method for rapidly producing an effective vaccine for any newly modified pathogen is needed, and genetic vaccines have exactly this potential, if methods for induction of strong mucosal immune responses can be developed. We propose to investigate the properties of oral delivery methods for DNA vaccines using plasmids encoding model antigens, a fragment of anthrax lethal toxin, and the cytokine IL12 to enhance the development of immune responses in mice, with particular emphasis on eliciting antibody and cytotoxic T cell responses in both mucosal and systemic sites.